Acute kidney injury (AKI) is a common disorder with an exceedingly high morbidity and mortality. Inflammation plays an important role in the pathogenesis of AKI. Molecules are exists to control inflammatory process however, the mechanisms through these molecules suppress inflammation and how inflammatory processes overcome the suppression to induce renal injury are remains poorly understood. The objective of this application is to determine the mechanisms by which activation of signaling pathways by netrin-1 lead to protection of kidney against ischemic reperfusion injury. Netrins are a family of neuronal guidance cues highly expressed in vascular endothelial cells and their receptors were expressed both in circulating leukocytes and endothelial cells. Our central hypothesis is that netrin-1 inhibits leukocyte migration and inflammation acting via the UNC5B receptor expressed on the leukocytes and vascular endothelial cells resulting in reduced inflammation and increased perfusion of the kidney. This hypothesis is based on our extensive preliminary data which clearly indicate that netrin-1 expression down regulated in endothelial cells after ischemia reperfusion of kidney and administration of recombinant netrin-1 protected ischemia reperfusion injury of the kidney and reduced inflammation. We plan to test our hypothesis and achieve the objective of this application by pursuing the following three specific aims: #1) Determine the receptor(s) which mediate netrin-1 protective effect against ischemia reperfusion of the kidney. #2) Determine the signaling mechanism through which netrin-1 mediates effect on renal parenchymal cells and leukocytes. #3) Determine the mechanism of netrin-1 mediated protection against ischemic renal injury. The proposed work is innovative because the role of netrin-1 and their receptors in AKI is unknown. Our expectation is that the results will provide novel insights into the mechanisms whereby netrin-1 signaling regulate inflammation and subsequent protection of structural and functional damage. It will also discover new information defining the regulation of epithelial and endothelial functions by netrin-1 signaling in response to ischemic renal injury. PUBLIC HEALTH RELEVANCE: The proposed studies will elucidate the key role of netrin-1 receptors in the netrin-1 mediated protection of kidney against ischemia reperfusion injury. They will also define the central role of kidney netrin-1 receptor signaling in regulating migration of inflammatory cells infiltrate into kidney. These results will be relevant because they are expected to lead to clinical trials to test the efficacy of recombinant netrin-1 and other signaling pathway inhibitors for the prevention or treatment of acute renal injury.